Neurogenesis impairment: An early developmental defect in Down syndrome
Abstract
Down syndrome (DS) is characterized by brain hypotrophy and intellectual disability starting from early life stages. Accumulating evidence shows that the phenotypic features of the DS brain can be traced back to the fetal period since the DS brain exhibits proliferation potency reduction starting from the critical time window of fetal neurogenesis. This defect is worsened by the fact that neural progenitor cells exhibit reduced acquisition of a neuronal phenotype and an increase in the acquisition of an astrocytic phenotype. Consequently, the DS brain has fewer neurons in comparison with the typical brain. Although apoptotic cell death may be increased in DS, this does not seem to be the major cause of brain hypocellularity. Evidence obtained in brains of individuals with DS, DS-derived induced pluripotent stem cells (iPSCs), and DS mouse models has provided some insight into the mechanisms underlying the developmental defects due to the trisomic condition. Although many triplicated genes may be involved, in the light of the studies reviewed here, DYRK1A, APP, RCAN1 and OLIG1/2 appear to be particularly important determinants of many neurodevelopmental alterations that characterize DS because their triplication affects both the proliferation and fate of neural precursor cells as well as apoptotic cell death. Based on the evidence reviewed here, pathways downstream to these genes may represent strategic targets, for the design of possible interventions.
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The reduction in neuron number appearing at and before birth supports the idea that the generation of neurons is reduced during the prenatal period in Down syndrome and establishes impaired neurogenesis as a key feature of Down syndrome.
“The fact that this reduction in neuron number appears at and before birth supports the idea that the generation of neurons is reduced during the prenatal period in DS and establishes impaired neurogenesis as a key feature of DS49,50 (Fig. 2).”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [50]
Analyses of fetal brain tissue indicate that there are fewer proliferating cells, as measured by expression of the cell cycle marker Ki67 and of cyclin proteins, in the germinal zones of the hippocampus and cortex in Down syndrome.
“Analyses of fetal brain tissue indicate that there are fewer proliferating cells, as measured by their expression of the cell cycle marker Ki67 and of cyclin proteins, in the germinal zones of the hippocampus and cortex in DS40,42–44,47,50,64.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [50]
The presence of fewer cycling cells and the reduced number of progenitors both support the suggestion that neurogenesis is reduced during development in Down syndrome, although these data do not distinguish between slower progenitor proliferation or premature progenitor cell cycle exit.
“Together, the presence of fewer cycling cells and the reduced number of progenitors both support the suggestion that neurogenesis is reduced during development in DS, although these data do not distinguish between slower progenitor proliferation or premature progenitor cell cycle exit.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [50]
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References 190 · Cited by 120
- Authors
- Stagni, F., Giacomini, A., Emili, M., Guidi, S., & Bartesaghi, R.
- Affiliations
- University of Bologna (IT)
- Corresponding author
- Bartesaghi, Renata
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 114
- Pages
- 15-32
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2740903678
- Cited by
- 120
- References
- 190
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 18 · 2023: 17 · 2022: 14 · 2021: 17 · 2020: 12 · 2019: 11 · 2018: 5 · 2017: 3
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Fondation Jerome Lejeune
- Fondazione Generali e Assicurazioni Generali
- Fondazione del Monte
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Down syndrome, neurogenesis, neural progenitor cells, intellectual disability, neuronal differentiation, apoptosis, DYRK1A, APP, RCAN1, neurodevelopmental defects, therapeutic target
- MeSH terms
- Animals, Down Syndrome, Humans, Nervous System Malformations, Neurogenesis, Neural Stem Cells
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